Abstract
Background and Objective Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by persistent inflammation affecting multiple organs, including the intestine. Lupus-derived gut inflammation can alter the epithelial barrier, where millions of commensals have a dynamic interaction with the host immune system. A new feature that seems to be decisive in autoimmune pathogenesis is the gut microbiota composition and its potential role. Our purpose is to elucidate the consequences of lupus gut inflammation locally and systemically and to characterize the relationship between SLE and microbiota composition.
Methods Lupus derived gut affectation was characterised by using a TLR7-mediated model of the disease. We assessed splenomegaly and anti-dsDNA autoantibodies by ELISA and the GALT IgA response by flow cytometry and ELISA. Gut permeability was evaluated using FITC-dextran and immunofluorescent staining of claudin-1 and occludin in the gut epithelium. Systemic response against microbiota was studied by ELISA and flow cytometry. The microbiota composition was analysed by V4 16S rRNA sequencing.
Results Overexpression of TLR7 induced a ‘leaky gut’ state with increased gut permeability and altered distribution of tight junction proteins. These alterations happened concomitantly with the onset of the disease, as characterised by splenomegaly and anti-dsDNA autoantibodies levels. TLR7Tg mice presented greater levels of GL7+ B220+ B cells within the Peyer’s patches, indicating elevated local immune activity. Specifically, disease inflammation altered the gut-associated immune response by readily increasing IgA+ B cell numbers and the levels of secreted IgA when compared with WT mice. Bacterial composition was determined, and the results revealed species differentially colonizing only the gut of TLR7Tg, being Bacteroides acidifaciens the most significant. Interestingly, TLR7Tg presented a differential IgM, IgA and IgG2a response against B.acidifaciens that was absent in WT mice. This B.acidifaciens response in TLR7Tg mice correlated significantly with systemic levels of total IgM and anti-dsDNA IgM.
Conclusion Altogether, we demonstrate that TLR7-induced SLE manifests by disrupting the gut barrier function and changing the gut-associated immune response and microbiota composition. This enables certain bacteria to translocate and induce a systemic immune response that could reinforce autoimmunity. Whether this immune response contributes to disease development is under investigation.
